Mucositis is a common serious side effect of high-dose chemotherapy (CT) and/or radiotherapy (RT) regimens often manifested as erythema and painful ulcerative lesions of the mouth, esophagus, pharynx and gastrointestinal tract that threatens the successful treatment of at least 600,000 people worldwide. These cytoreductive therapies aimed at killing cancer cells can also indiscriminately destroy other fast-growing cells such as the lining of the mouth and throat and gastrointestinal tract.
The development of mucositis is a complex process. Typically, mucositis symptoms develop 5 to 8 days following the administration of CT and last approximately 7 to 14 days. The pathobiology of mucositis is currently defined as a 5-phase process: initiation, signaling with generation of messengers, amplification, ulceration, and, finally, healing.
Oral and gastrointestinal (GI) mucositis can affect up to 100% of patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. For most cancer treatments, about 5-15% of patients get mucositis. However, with 5-fluorouracil (5-FU), up to 40% get mucositis, and 10-15% get grade 3-4 oral mucositis. Irinotecan treatment is associated with severe GI mucositis in over 20% of patients. 75-85% of bone marrow transplantation recipients experience mucositis, of which oral mucositis is the most common and most debilitating, especially when melphalan is used. In grade 3 oral mucositis, the patient is unable to eat solid food, and in grade 4, the patient is unable to consume liquids either. Radiotherapy to the head and neck or to the pelvis or abdomen is associated with grade 3 and grade 4 oral or GI mucositis, respectively, often exceeding 50% of patients. Among patients undergoing head and neck radiotherapy, pain and decreased oral function may persist long after the conclusion of therapy. Fractionated radiation dosage increases the risk of mucositis to >70% of patients in most trials.
Oral mucositis has been identified as the most debilitating side effect of anticancer therapy by patients who experienced it while undergoing myelotoxic therapy for hematopoietic stem cell transplant, which is associated with the greatest degree of mucosal toxicity with 70%-80% of patients suffering from oral mucositis. Consequent morbidities of severe oral mucositis can include pain severe enough to require opioid analgesia, difficulty or inability to swallow due to ulcerations in the mouth and throat, which, if severe, may necessitate total parenteral nutrition (TPN) and rehydration, difficulty or inability to talk, which can hinder patients' abilities to communicate. Of significance, the development of oral mucositis often precludes oncologists from prescribing a full dose and regimen of chemotherapy or radiation therapy so that the disease frequently limits the potential full benefit of possibly curative treatments. The burden of oral mucositis development has been estimated to add $4,000 to hospital costs for patients with head and neck cancers to $43,000 for undergoing patients bone marrow transplant.
Managing oral mucositis is primarily supportive. There are many different methods to help relieve the pain, including sucking on ice cubes, antioxidants, and mouth rinses. Several mouth rinses are available that combine antihistamines, anesthetics, anti-inflammatory medications (such as corticosteroids), antibiotics, and antifungals. Narcotic analgesics may also prove to help relieve the pain. Other methods include antimicrobials, anti-inflammatories, and good oral care.
Palifermin (KEPIVANCE®) (human keratinocyte growth factor (KGF)) is the only drug approved for oral mucositis and is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support/transplantation. However, HSCT represents a small subset of the cancer population and most solid tumors carry KGF receptors, through which this agent might have potentially undesired agonist effect. Thus, application of palifermin (KEPIVANCE®) to the larger market of cancers and consequent oral mucositis resulting from treatment thereof is extremely unlikely. Additional indication studies beyond HSCT are currently being done, and include use of the drug in graft versus host disease, head and neck cancers, Stage 2/3 colon cancer multiple myeloma, lymphoma and leukemia, and pediatric HSCT populations.
Thus, there remains a significant unmet need in the treatment of mucositis.